# Glia Exclusive Gene Therapy

> **NIH NIH R21** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $198,750

## Abstract

Abstract
Glia are supportive cells in the human brain, comprising microglia, oligodendrocytes, astrocytes, and ependymal cells.
Glia are deeply involved in diseases of the nervous system such as Alzheimer’s (AD), autism, pain, affective disorders,
and cancers. Different glial cell types play different mechanistic roles in disease formation, driven by specific genes.
Modulating glial gene expression via a process called gene therapy could thus be studied as a means of preventing
deleterious effects of glia in the brain. However, while significant progress has been made in delivering genes exclusively
to neurons, such capabilities are lacking for glia, despite their demonstrated role in disease formation, posing a critical
medical need. Although gene delivery to neurons can be achieved using viral vectors, their use to transmit genes to glia
in-vivo has been unsuccessful. Here, we propose to design a novel nonviral gene delivery vector targeting microglia or
astrocytes exclusively by bioengineering Modified RNAs (ModRNAs). ModRNAs are synthetic RNA molecules known
not to trigger an immune response and are strongly expressed in target cells. Currently, ModRNAs enable only days-
long expression, impeding long-duration medical applications and lacking cell specificity to glia types. We will engineer
glia-type-specific, ModRNAs-based constructs, GliaRNAs, as a platform for glia-exclusive gene therapy, with a
customizable expression duration. First, ModRNAs that enable robust and prolonged expression (7-14 days) will be
developed (Aim 1). For this purpose, existing ModRNA will be altered, through modifications and by inflicting random
mutations of structural components of the molecule, including CAP analog, 3’ untranslated region, coding region, 5’
untranslated region, and the poly-A tail. We will test the expression of these novel GliaRNAs in glial cultures from mice.
Next, the vector specificity will be optimized (Aim 2). We will screen for molecular manipulations that enable robust and
specific delivery of the GliaRNAs into either microglia or astrocytes (GliaRNA-vectors) and select the best gene delivery
vectors, specifically either lipid nanoparticles, antibody-lipid conjugates, or aptamers. As a proof of concept, we will use
the new GliaRNA-vector technology to express the green fluorescent protein (GFP) in either astrocytes or microglia in
mice brains. The GliaRNA-vector platform will pave the way for genetically healing and modifying different types
of glia, opening multiple therapeutic and research avenues in humans by targeting neurodegeneration, autism,
pain disorders, mood disorders, and brain cancers.

## Key facts

- **NIH application ID:** 10881987
- **Project number:** 5R21EB033121-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Or Shemesh
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $198,750
- **Award type:** 5
- **Project period:** 2023-07-15 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10881987

## Citation

> US National Institutes of Health, RePORTER application 10881987, Glia Exclusive Gene Therapy (5R21EB033121-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10881987. Licensed CC0.

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